An integrated fragment based screening approach for the discovery of small molecule modulators of the VWF–GPIbα interaction

Jose, Rani A.; Voet, Arnout; Broos, Katrijn; Jakobi, Arjen J.; Bruylants, Gilles; Egle, Brecht; Zhang, Kam Y. J.; Maeyer, Marc De; Deckmyn, Hans; Borggraeve, Wim M. De

doi:10.1039/c2cc35269a

Cited by 10 publications

(4 citation statements)

References 28 publications

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“…One of the key advantages of this approach is the more efficient coverage of chemical space by compounds of lower molecular weight, requiring smaller screening libraries compared with HTS. In the context of PPIs, numerous examples of inhibitors have been identified using this approach ( Abdel-Rahman et al., 2011; Douse et al., 2015; Gao et al., 2014; Holvey et al., 2015; Jose et al., 2012; Lund et al., 2015; Molzan et al., 2012; Moore et al., 2009; Patrone et al., 2013; Van Molle et al., 2012; Yin et al., 2014 ). Prominent examples include the Bcl-2 inhibitor ABT-737 ( Oltersdorf et al., 2005 ), inhibitors of the RAS oncogene ( Maurer et al., 2012 ), and inhibitors of the BET bromodomains ( Chung et al., 2012 ).…”

Section: Main Textmentioning

confidence: 99%

Overcoming Chemical, Biological, and Computational Challenges in the Development of Inhibitors Targeting Protein-Protein Interactions

Laraia

McKenzie

Spring

et al. 2015

Chemistry & Biology

136

107

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Protein-protein interactions (PPIs) underlie the majority of biological processes, signaling, and disease. Approaches to modulate PPIs with small molecules have therefore attracted increasing interest over the past decade. However, there are a number of challenges inherent in developing small-molecule PPI inhibitors that have prevented these approaches from reaching their full potential. From target validation to small-molecule screening and lead optimization, identifying therapeutically relevant PPIs that can be successfully modulated by small molecules is not a simple task. Following the recent review by Arkin et al., which summarized the lessons learnt from prior successes, we focus in this article on the specific challenges of developing PPI inhibitors and detail the recent advances in chemistry, biology, and computation that facilitate overcoming them. We conclude by providing a perspective on the field and outlining four innovations that we see as key enabling steps for successful development of small-molecule inhibitors targeting PPIs.

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Section: Main Textmentioning

confidence: 99%

Overcoming Chemical, Biological, and Computational Challenges in the Development of Inhibitors Targeting Protein-Protein Interactions

Laraia

McKenzie

Spring

et al. 2015

Chemistry & Biology

136

107

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“…Ideally, a fragment screening technique enables rank-ordering of hits according to their affinity. Due to recent reports on rank-ordering hits from STD NMR screening and counter-screening applying the STD amplification factor (Jose et al, 2012; Begley et al, 2013; Cala and Krimm, 2015), we retrospectively analyzed a fragment screening against langerin, a C-type lectin receptor involved in pathogen uptake by immune cells (Aretz et al, 2018). Here, fragments were screened by STD NMR, and the affinity of hits was subsequently estimated by SPR (Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

Ranking Hits From Saturation Transfer Difference Nuclear Magnetic Resonance–Based Fragment Screening

Aretz

Rademacher

2019

Front. Chem.

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Fragment-based screening is an established route to identify low-molecular-weight molecules to generate high-affinity inhibitors in drug discovery. The affinities of these early hits from fragment screenings require a highly sensitive biophysical screening technique. Saturation transfer difference (STD) nuclear magnetic resonance (NMR) is one of the most popular methods owing to its high sensitivity for low-affinity ligands. It would be highly beneficial if rank-ordering of hits according to their affinity from an initial or counter-screen could be performed—a selection criterion found in the literature. We applied Complete Relaxation and Conformational Exchange Matrix (CORCEMA) theory adapted for saturation transfer (ST) measurements (CORCEMA-ST) calculations to predict STD NMR results from a large set of fragment/receptor pairs to investigate the boundaries under which the assumption holds true that a high STD effect can be applied to select for higher-affinity fragments. Overall, we come to the conclusion that this assumption is invalid.

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“…A summary of these compounds is shown in Table S1. † Although stimulators are uninteresting for our current research, they indicate the possibility of PPI-stimulation and together with recent reports 23,24 may provide an interesting type of drug candidate in the future. For further validation of the most potent SMPPII hit compounds, a Surface Plasmon Resonance (SPR) assay was employed (Table S1 †).…”

mentioning

confidence: 83%

Discovery of small molecule inhibitors targeting the SUMO–SIM interaction using a protein interface consensus approach

et al. 2014

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An integrated fragment based screening approach for the discovery of small molecule modulators of the VWF–GPIbα interaction

Abstract: An integrated approach comprising STD NMR screening, pharmacophore based analogue selection and a bioassay is presented for the discovery of a stabilizer of the clinically relevant VWF-GPIbα protein-protein interaction.

Cited by 10 publications

References 28 publications

Overcoming Chemical, Biological, and Computational Challenges in the Development of Inhibitors Targeting Protein-Protein Interactions

Overcoming Chemical, Biological, and Computational Challenges in the Development of Inhibitors Targeting Protein-Protein Interactions

Ranking Hits From Saturation Transfer Difference Nuclear Magnetic Resonance–Based Fragment Screening

Discovery of small molecule inhibitors targeting the SUMO–SIM interaction using a protein interface consensus approach

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